Combined immunosuppressive therapy with low dose FK506 and antimetabolites in rat allogeneic heart transplantation

Transplantation
M TanabeT E Starzl

Abstract

Following rat heterotopic heart allotransplantation, low to lethal doses of the antimetabolites mizoribine (MIZ), RS-61443 (RS), and AZA were given alone or in combination with subtherapeutic doses of FK506 (0.04 mg/kg/day) for 14 days after transplantation. With the median effect analysis of Chou and Kahan for quantitative drug interactions, substantial therapeutic synergism was demonstrated between FK506 and non-toxic doses of MIZ (2.5, 5, and 10 mg/kg/day) or AZA (5, 30, and 45 mg/kg/day), which was particularly evident with the lowest dose MIZ (2.5 mg/kg/day). When FK506 was used in combination with MIZ or AZA but not with RS, the maximum effect (peak median graft survival) was enhanced significantly from 15 days (MIZ alone) to 26 days (P < 0.05), and from 19 days (AZA alone) to 32 days (P < 0.01). In contrast, RS interacted with FK506 no more than additively. Although RS was the most powerful single antimetabolite, the best overall survival was obtained by combining AZA and FK506. The addition of FK506 did not significantly increase the percent mortality and LD50 of the antimetabolites.

References

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Apr 7, 1989·Science·G B Elion
Feb 1, 1969·The Journal of Thoracic and Cardiovascular Surgery·K Ono, E S Lindsey

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Citations

Jan 9, 1998·Transplantation·F S ShihabT F Andoh
Jan 1, 1996·Transplant International : Official Journal of the European Society for Organ Transplantation·R L MarquetJ N IJzermans
Aug 21, 2013·Transplant International : Official Journal of the European Society for Organ Transplantation·Raimund H M PreidlStephan M Ensminger
Jul 5, 2005·Expert Opinion on Investigational Drugs·M Behrend
Feb 1, 1997·American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation·M R First

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